Abstract
Naïve CD4+ T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. The differentiation of pro-inflammatory TH1 and anti-inflammatory Foxp3+ regulatory T cells (Treg) was reciprocally regulated by S1P1, a receptor for the bioactive lipid sphingosine-1-phosphate. S1P1 inhibited extrathymic and natural Treg generation while driving TH1 cell development in a reciprocal manner and disrupted immune homeostasis. S1P1 signaled through mTOR and antagonized TGF-β function mainly by attenuating sustained Smad3 activity. S1P1 function was dependent upon endogenous sphingosine kinase activity. Remarkably, two seemingly unrelated immunosuppressants FTY720 and rapamycin targeted the same S1P1 and mTOR pathway to regulate the dichotomy between TH1 and Treg cells. Our studies establish an S1P1-mTOR axis that controls T cell lineage specification.
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